title: Nitroreductase (GlNR1) increases susceptibility of Giardia lamblia and Escherichia coli to nitro drugs.
abstract: OBJECTIVE
  The protozoan parasite Giardia lamblia causes the intestinal disease giardiasis, which may lead to acute and chronic diarrhoea in humans and various animal species. For treatment of this disease, several drugs such as the benzimidazole albendazole, the nitroimidazole metronidazole and the nitrothiazolide nitazoxanide are currently in use. Previously, a G. lamblia nitroreductase 1 (GlNR1) was identified as a nitazoxanide-binding protein. The aim of the present project was to elucidate the role of this enzyme in the mode of action of the nitro drugs nitazoxanide and metronidazole.
  
  
  METHODS
  Recombinant GlNR1 was overexpressed in both G. lamblia and Escherichia coli (strain BL21). The susceptibility of the transfected bacterial and giardial cell lines to nitazoxanide and metronidazole was analysed.
  
  
  RESULTS
  G. lamblia trophozoites overexpressing GlNR1 had a higher susceptibility to both nitro drugs. E. coli were fully resistant to nitazoxanide under both aerobic and semi-aerobic growth conditions. When grown semi-aerobically, bacteria overexpressing GlNR1 became susceptible to nitazoxanide.
  
  
  CONCLUSIONS
  These findings suggest that GlNR1 activates nitro drugs via reduction yielding a cytotoxic product.
authors.affiliation: Institute of Parasitology, University of Berne, Berne, Switzerland.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nillius
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller
authors.forename: Norbert
authors.initials: N
authors.lastname: Müller
mesh_terms: D000890:Anti-Infective Agents / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology*; D016829:Giardia lamblia / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008795:Metronidazole / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology*; D009601:Nitroreductases / Q000378:metabolism*; D010084:Oxidation-Reduction; D021261:Parasitic Sensitivity Tests; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D009574:Nitro Compounds; D013844:Thiazoles; D008795:Metronidazole; D009601:Nitroreductases; C041747:nitazoxanide